FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"TOPICAL FORMULATION CONTAINING ETODOLAC"
2. APPLICANT
(a) NAME: Lyka Labs Limited.
(b) NATIONALITY: Indian Company incorporated under the
Indian Companies Act, 1956
(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri-Kurla Road,
Andheri (East), Mumbai - 400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention:


Technical field of invention:
The present invention relates to a topical formulation such as gel, emulgel containing an NSAID, most favorably, Etadolac and the process for preparations thereof. The said formulation also comprises therapeutically effective amount of Methyl Salicylate, and Menthol which is useful for relief of pain and inflammation in patients suffering form Osteoarthritis, Rheumatoid arthritis, soft tissue Rheumatism, sprain and low back ache.
Background of the invention:
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs, probably due to their therapeutic properties as anti-inflammatories, analgesics, anti¬pyretics, and anti-thrombolies and are used to treat a variety of clinical conditions manifesting such symptoms as pain, inflammation, fever, and to treat and prevent atherosclerosis.
While these drugs are highly effective, oral administration of many NSAIDs can cause serious adverse effects such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances, particularly after extended use. Therefore, in an effort to minimize the adverse effects associated with oral administration, non-oral delivery of NSAIDs has been extensively investigated in recent years.
Transdermal delivery of NSAIDs is particularly useful for treatment of rheumatoid arthritis and related conditions, which are characterized by painfiil and swollen joints due to inflammation in the musculoskeletal tissues of the joints. However, although topical administration of certain NSAIDs has been shown to deliver the drug to the local musculoskeletal tissues of joints where arthritic conditions often develop, due to the low solubility of NSAIDs in water, the effectiveness of topical administration of NSAIDs is limited by the inability of these drugs to permeate the skin.
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Etodolac is a member of the pyranocarboxylic acid group of non-steroidal anti¬inflammatory drug (NSAIDS). Etodolac is NSAID that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. It is effective in treating fever, pain, and inflammation in the body.
The mechanism of action of etodolac like that of other NSAIDs is not completely understood but may be related to prostaglandin synthetase inhibition.
Etodolac is a racemic of [-] R - and [+]S-etodolac as with other NSAIDs, it has been demonstrated in animals that the [+}s-form is biologically active. Chemically Etodolac is 2-(l,8-Diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-l-yl)acetic acid having structural formula as follows

Methyl salicylate (chemical formula C6H4(HO)COOCH3; also known as salicylic acid methyl ester, oil of wintergreen, betula oil, methyl-2-hydroxybenzoate) is a natural product of many species of plants. Some of the plants producing it are called wintergreens. Methyl Salicylate has a following structural formula:
o

Methyl Salicylate is a counter irritant. Methyl Salicylate is a widely used topical counter irritant. Methyl Salicylate provides the following benefits: 1) Counter irritation leads to vasodilatation.
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2) Counter irritant act through the peripheral reflux network which is known to provide analgesic action.
3) The effect is mainly on 'C-fiber' which carry sensory impulses.
Methyl Salicylate being counter irritant also alters the physicochemical nature of the stratum corneum and thus reduces diffusion reinforce of Etodolac.
Menthol is an organic compound made synthetically or obtained from peppermint or other mint oils. Menthol has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation.Menthol causes vasodilatation and has cooling effect at the site of application. Chemically Menthol is (lR,2S,5R)-2-isopropyl- 5-methylcyclohexanol, C10H20O , having structural formula as follows:

A Topical Formulation comprising Methyl Salicylate & Menthol is available in the market under brand name BenGay, Icy Hot, Mentholatum Deep Heat used to relieve pain of muscle aches and sprains, rheumatism, arthritis and similar conditions. However the said formulation has certain side effect such as Redness or irritation may occur, especially in persons with sensitive skin. If this continues or skin becomes itchy, swollen. One can develop a rash, ringing in the ears, nausea or vomiting.
A Lotion is available in market comprising Methyl Salicylate/Benzocaine/Menthol which is a topical analgesic. It works by temporarily relieving minor pain.
US Patent No. 7132452 discloses topical formulation containing NSAID, particularly diclofenac having effects on alleviating pain/inflammation caused by herpes virus infection. The said NSAID may also optionally include etodolac, ketorolac, bromfenac, diflunisal, ibuprofen, fenoprofen, ketoprofen, naproxen, suprofen, meclofenamate,
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oxyphenbutazone, and tolmetin.
US Patent No. 5976566 topical alcoholic or aqueous alcoholic gels containing ibuprofen or other NSAIDs, such as, naproxen, in substantially neutral salt form, have enhanced penetration through skin and may provide rapid pain/inflammation relief by including in the formulation 2-n-nonyl-l,3-dioxolane or other hydrocarbyl derivative of 1,3-dioxolane or 1,3-dioxane or acetal, as skin penetration enhancing compound.
" None of the prior arts talk about the gel composition comprising Etodolac or Etodolac with Methyl Salicylate/Menthol. Present invention particularly relates to emulgel/gel of Etadolac/ Methyl Salicylate/Menthol for treatment of relief of pain and inflammation in patients suffering form Osteoarthritis, Rheumatoid arthritis, soft tissue Rheumatism, sprain and low back ache.
Object of the invention:
The present invention relates to a topical formulation in form of gel, emulgel containing an NSAID, most favorably, Etodolac and therapeutically effective amount of Methyl Salicylate and Menthol and the process for preparations thereof.
Summary of the Invention:
The present invention discloses a pharmaceutical composition comprising therapeutically effective amount of Etodolac, Methyl Salicylate, Menthol in the form of gel, emulgel along with pharmaceutically acceptable excipients comprising Gelling agent, Co-solvent, pH adjusting agent and optionally Buffering agent, Chelating agent, antioxidant, preservatives and purified water as suitable vehicle.
In another embodiment, the present invention provides a process for the manufacture of Etadolac gel and emulgel. The said topical formulation is useful for relief of pain and inflammation in patients suffering form Osteoarthritis, Rheumatoid arthritis, soft tissue Rheumatism, sprain and low back ache.
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Detailed description of the invention:
The present invention describes topical composition comprising 1% - 6%w/w of Etodolac, 0%-20% of Methyl Salicylate, and 0-7% of Menthol.
In accordance to the above objectives, the present invention provides the topical composition in the form of gel and emulgel which comprises therapeutically effective amount of Etadolac, Methyl Salicylate and Menthol, alongwith pharmaceutically accepted ingredients.
The gel composition of Etodolac comprises of Gelling agent such as Carbomers such as Carbopol 980 in the range of 0.5-2.0%w/w.
Co-solvents are selected from the group of PropyJene GJycoJ, polyethyJene glycol or Isopropyl Alcohol or combination thereof in the range of 5-80% w/w.
pH of the gel is adjusted using pH adjusting agents such as Triethanolamine alongwith a suitable vehicle/carrier is used such as Purified Water.
The emulgel composition comprises of Gelling agent selected from the group of Carbomers such as Carbopol 980 and Hydroxy Propyl Cellulose in the range of 0.5-3%w/w.
Co-solvent selected from the group of Propylene Glycol and Isopropyl Alcohol in the range of 5-80% w/w.
pH of the emulgel is adjusted by pH adjusting agent such as Triethanolamine and Diethanol amine.
Buffering agent such as Citric acid anhydrous is used in the range of 0.01-0.1%.
Surfactant such as Cremophore RH 40 is used in the range of 2-5%.
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Further, Chelating agent such as Disodium EDTA is used in the range of 0.005-0.2%.
Anti oxidant selected from Butylated Hydroxy Toluene in the range of 0.1-0.5% and a-Tocopherol in the range of 0.01 -0.15%.
Preservatives such as Benzyl Alcohol, Methyl Paraben and Propyl Paraben are used in the range of 0.01-0.25%.
The following examples are for the purpose of illustration of invention only and are not intended in any way to limit the scope of the invention.
Example 1:
Etodolac Gel comprising 1% - 6% w/w of Etodolac
This formulation may be prepared by soaking carbopol in purified water overnight. Etodolac may be dissolved in co-solvent such as propylene glycol, polyethylene glycol or Isopropyl alcohol or combination thereof. Surfactant like Cremophore RH 40 may be added to enhance the solubility of Etodolac. Etodolac solution may be added to carbopol gel and mixed properly, then by adjusting pH with Triethanolamine solution till gel formation takes place. pH may be adjusted in the range of 4.5 - 5.5.
- Composition for the preparation of gel is as follows.

Active ingredient Etodolac l%-6%w/w
Gelling agent Carbomers such as
Carbopol 980 0.5-2.0%w/w
Co-solvent Propylene Glycol 5-80% w/w
Isopropyl Alcohol
Surfactant Cremophore RH 40 2-5%
pH adjusting agent Triethanolamine
Vehicle Purified Water
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Example 2:
Etodolac Emulgel comprising of J % - 6%w/w of Etodolac
This preparation may be prepared with one or more other active ingredients such as
Menthol 5%w/wand Methyl Salicylate 10%w/w.
This preparation may be prepared by making slurry of Carbopol in water. Chelating agent
such as Disodium EDTA may be dissolved in purified water and added to the carbopol
slurry pH of the slurry may be adjusted with pH adjusting agent such as Diethanolamine
or Triethanolamine to about 4.5 till gel formation takes place.
Methyl Salicylate may be mixed properly with Isopropyl alcohol and surfactants like
Cremophor RH 40 (part qty) till clear solution is obtained. Menthol may be dissolved in
the methyl Salicylate solution
Etodolac may be dissolved in co-solvent such as Propylene Glycol and Isopropyl
Alcohol. Surfactant like Cremophore RH 40 (part qty) may be added. Preservative may
be added to this solution. Anti-oxidant such as Butylated hydroxy toluene may be added
to this. Solution may be stirred well to get clear solution
Optionally Linseed oil may be mixed with Methyl Salicylate solution with fast stirring for
emollient action.
Buffering agent such as Citric Acid anhydrous may be dissolved in purified water.
Methyl salicylate solution with Menthol may be added to the Carbopol gel.
Then Etodolac solution may be added to the bulk gel.
Then buffering agent solution may be added to the bulk and final weight may be adjusted
with purified water pH may be checked .which may be around 4.0 to 6.0.
Composition of the preparation may be as follows.

Active ingredient Etodolac 1%-6%W/W
Methyl Salicylate 10%w/w
Menthol 5% w/w
Gelling agent Carbopol 980 0.5-2.0% w/w
Hydroxy Propyl Cellulose 0.5-3%
Co-solvent Propylene Glycol 5-80% w/w
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Isopropyl Alcohol
pH adjusting agent Triethanolamine q.s.
Diethanol amine q.s.
Buffering agent Citric acid anhydrous 0.01-0.1%
Surfactant Cremophore RH 40 2-5%
Chelating agent Disodium EDTA 0.005-0.2%
Anti oxidant Butylated Hydroxy Toluene 0.1-0.5%
ct-Tocopherol 0.01-0.15%
Preservative Benzyl Alcohol
Methyl paraben 0.05-0.25%
Propyl paraben 0.01-0.1%
Vehicle Purified Water
Dated this 18tn day of September 2008
Dr. Aruna Sree Agent for the applicant
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